PROJECT SUMMARY Project 2, Risk Factors for Fractures Among the Elderly, complements this Program Project Grant (PPG) by providing a population perspective on risk factors for age-related fractures. In each of our Aims, we propose to continue our focus on identifying risk factors for long-term fracture outcomes by conducting large, historical cohort studies of Olmsted County (OC), Minnesota residents. Such studies are made possible by the unique medical-records linkage system of the Rochester Epidemiology Project (REP) infrastructure, through which complete information (inpatient and outpatient) on medical care of OC residents is available. We will further strengthen our interpretation of results from these large cohort studies by directly measuring bone density and microstructure as well as performing comprehensive assessments of additional risk factors for fractures in the relavent population groups being studied in each Aim. In Aim 1, we will focus on updating the fracture risk in a common age-related comorbid condition, heart failure (HF), given recent data suggesting that HF patients on -blockers (which recently has become the standard-of-care) may, in fact, now be protected against low bone density and fractures. By performing a comprehensive evaluation of fracture risk in individuals with chronic HF in the era of widespread -blocker therapy, we will address the central theme of this PPG, sympathetic nervous system (SNS) control of bone metabolism, and complement the work being performed by the other Projects in this PPG, which are evaluating the detrimental effects on bone of increased sympathetic activation (also an underlying mechanism for HF) and potential beneficial effects of -blockers (which antagonize sympathetic activation) on bone metabolism. In Aim 2, we will expand on our prior work by now performing a systematic examination of all comorbid conditions in older OC residents in order to improve fracture risk assessment. Using innovative analytic techniques, we will describe the emergence and interrelation of multiple comorbidities with aging and test whether specific fractures are preceded by different comorbidity clusters, and specifically examine how they may affect bone density. These population-based studies will fill important gaps in our knowledge and provide novel insights on age-related fracture risk.